Source: Marketing Authorisation Holder Revision Year: 2020 Publisher: Activo Health (Pty) Ltd. Block B, Arena Office Park, 272 West Avenue, Centurion, 0157
Pharmacological classification: A 7.5 Serum-cholesterol reducers.
Atorvastatin is a fully synthetic cholesterol-lowering agent. It is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol. As a result, in patients with hyperlipidaemias, including hypercholesterolaemias and combined (mixed) hyperlipidaemia (type Ila or Ilb hyperlipoproteinaemias), hypertriglyceridaemia (type IV), and dysbetalipoproteinaemia (type III), atorvastatin reduces total plasma cholesterol, low-density lipoprotein (LDL-C)- and very low density lipoprotein (VLDL-C)-cholesterol concentrations, triglycerides and apolipoprotein B. In addition, atorvastatin increases high-density lipoprotein (HDL-C)-cholesterol. Atorvastatin exerts its main effect in the liver.
Atorvastatin is administered in an active (open) form without the need for hydrolysis. It is rapidly absorbed from the gastrointestinal tract, with maximum concentration being achieved in 1 to 2 hours. It has a low absolute bioavailability of the parent compound of about 12%, due to presystemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver, its primary site of action.
LDL-C reduction is similar whether atorvastatin is given with or without food, despite a decreased rate and extent of absorption when given with food. LDL-C reduction is the same regardless of the time of administration, despite lower atorvastatin plasma concentrations following evening administration compared to morning administration.
Atorvastatin is 98% or more bound to plasma proteins.
Atorvastatin is metabolised by the cytochrome P450 isoenzyme CYP3A4 to a number of active metabolites (ortho- and parahydroxylated derivatives and various beta-oxidation products). The ortho- and parahydroxylated metabolites are pharmacologically active and their in vitro inhibition of HMG-CoA reductase activity is equivalent to the parent compound.
The mean plasma elimination half-life of atorvastatin is about 14 hours, although the half-life of inhibitory activity for HMG-CoA reductase is about 20 to 30 hours due to the contribution of the active metabolites. Atorvastatin is excreted as metabolites, primarily in the bile. Less than 2% is excreted renally.
Lipid lowering effects in the elderly are comparable to those in young adults at equal doses, despite higher plasma concentrations of atorvastatin in healthy elderly subjects.
Pharmacokinetic data in the paediatric population are not available.
Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B); see CONTRA-INDICATIONS.
Renal impairment has no influence on plasma concentrations; therefore dose adjustment is not needed; see WARNINGS.
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